Abstract 3329: Myocardial Loss of Ets2 Results in Dilated Cardiomyopathy in Adult Mice
Ets2 is a member of the ETS transcription factor gene family. Ets factors regulate the expression of genes encoding cell-cycle regulators, matrix metalloproteinases, cytokeratins, adhesion molecules, and growth factors thereby controlling cellular processes including proliferation, differentiation, transformation and apoptosis. Despite the detection of Ets2 mRNA in fetal and adult hearts by Northern blot, its embryonic and postnatal cardiac expression and function are poorly understood. To better understand the role of Ets2 in cardiac development, we examined its expression by in situ hybridization pattern during mouse cardiogenesis. At embryonic day 9.5 (E9.5), we observed Ets2 expression in the endocardium of the ouflow tract and atrio-ventricular canal. By E 10.5, in addition to the endocardium, Ets2 is detected in the myocardium of the atria and ventricles. By E 11.5, Ets2 expression is still detected in the myocardium and the endocardium of the four chambers. At later stages (E 12.5 –14.5), this expression pattern is maintained. By intercrossing Ets2 flox/flox and αMHC-Cre mice, we obtained animals (Ets2 myo−/−) deficient for Ets2 specifically in the myocardium. These animals are viable and appear normal, but die suddenly at 6 months of age. At necropsy, mice exhibit significant atrial and ventricular enlargement. Histopathological analysis reveals interstitial fibrosis and myocardial disorganization. Resting electrocardiography of 5 month old Ets2 myo−/− mice reveals a marked reduction in QRS voltage and varying interventricular conduction delays. Echocardiographic assessment reveals biatrial and biventricular chamber dilatation with 2–3 fold decreases in fractional shortening and ejection fraction. Immunohistochemical analysis of mutant hearts shows impaired intercalated discs organization with altered expression and localization of N-cadherin and Cx43. Our findings demonstrate a novel critical transcriptional requirement for Ets2 in the maintenance of adult cardiac morphology and function, whereby loss of Ets2 leads to dilated cardiomyopathy.